Orlistat

Cyclosporine: Reduction in cyclosporine plasma levels was observed when XENICAL was coadministered with cyclosporine. ( 7.1 ) Fat-soluble Vitamin Supplements and Analogues: All patients should take a daily multivitamin that contains vitamins A, D, E, K, and beta-carotene. ( 7.2 ) Levothyroxine: Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. ( 7.3 ) Warfarin: Patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. ( 7.4 ) Amiodarone: A reduction in exposure to amiodarone was observed when XENICAL was co-administered.

( 7.5 ) Antiepileptic Drugs: Convulsions have been reported in patients taking XENICAL with antiepileptic drugs. Patients should be monitored for possible changes in frequency or severity of convulsions. ( 7.6 ) Antiretroviral Drugs: Loss of virological control has been reported in HIV-infected patients. Patients should be monitored frequently for changes in HIV RNA levels. ( 7.7 )

7.1 Cyclosporine Data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. XENICAL and cyclosporine should not be simultaneously coadministered. Cyclosporine should be administered 3 hours after the administration of XENICAL [see Dosage and Administration (2) , and Warnings and Precautions (5.1) ] .

7.2 Fat-soluble Vitamin Supplements and Analogues Data from a pharmacokinetic interaction study showed that the absorption of beta-carotene supplement is reduced when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement. The effect of XENICAL on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time [see Clinical Pharmacology (12.3) , and Warnings and Precautions (5.1) ] .

7.3 Levothyroxine Hypothyroidism has been reported in patients treated concomitantly with XENICAL and levothyroxine postmarketing. Patients treated concomitantly with XENICAL and levothyroxine should be monitored for changes in thyroid function. Administer levothyroxine and XENICAL at least 4 hours apart [see Dosage and Administration (2) ] .

7.4 Anticoagulants including Warfarin Vitamin K absorption may be decreased with XENICAL. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with XENICAL and anticoagulants. Patients on chronic stable doses of warfarin or other anticoagulants who are prescribed XENICAL should be monitored closely for changes in coagulation parameters [see Clinical Pharmacology (12.3) ] .

7.5 Amiodarone A pharmacokinetic study, where amiodarone was orally administered during orlistat treatment, demonstrated a reduction in exposure to amiodarone and its metabolite, desethylamiodarone [see Clinical Pharmocology (12.3) ] . A reduced therapeutic effect of amiodarone is possible. The effect of commencing orlistat treatment in patients on stable amiodarone therapy has not been studied.

7.6 Antiepileptic Drugs Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugs. Patients should be monitored for possible changes in the frequency and/or severity of convulsions.

7.7 Antiretroviral Drugs Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with antiretroviral drugs such as atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, and with the combinations lopinavir/ritonavir and emtricitabine/efavirenz/tenofovir disoproxil fumarate. The exact mechanism for this is unclear, but may include a drug-drug interaction that inhibits systemic absorption of the antiretroviral drug. HIV RNA levels should be frequently monitored in patients who take XENICAL while being treated for HIV infection. If there is a confirmed increase in HIV viral load, XENICAL should be discontinued.

8.1 Pregnancy Pregnancy Category X XENICAL is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to the obligatory weight gain that occurs in maternal tissues during pregnancy. No embryotoxicity or teratogenicity was seen in animals that received orlistat at doses much higher than the recommended human dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus. Animal Data Reproduction studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/m 2 ) basis for rats and rabbits, respectively.

8.3 Nursing Mothers It is not known if XENICAL is present in human milk. Caution should be exercised when XENICAL is administered to a nursing woman.